This is a response to RFA-DA-04-005, which requests proposals for studies that describe and evaluate innovative drug abuse phenotypes that will inform and refine investigations into genetic risk. The overall goal of this proposal is to use a multigenerational perspective and an extensive assessment of multiple domains of functioning to systematically and precisely develop familial SUD phenotypes that can be informative to genetic studies. Future molecular genetic studies may thus be more fruitful if they focus on these alternative phenotypes explicitly developed to maximize their power to detect genes. Within the context of families ascertained from a referred ADHD youth, we will determine what clinical and functional phenotypic features are more common among subjects with SUDs than those without SUDs, and whether these features are stable over time. We will then examine whether these phenotypes are transmitted through families and if the strength of this transmission is related to SUDs. We will also investigate the familial association between SUDs and comorbid mood and antisocial disorders. We will then assess the specificity of these findings by replicating these analyses in families ascertained by youth with bipolar disorder. Throughout this research, we will test the effect of gender on the expression and familiality of these novel phenotypes. Following the recommendation of the RFA, we will capitalize on existing data sources that will provide us with ample statistical power, considerable cost-effectiveness and broad generalizability. We will use several identically designed case-control family-genetic studies of youth ascertained by a diagnosis of ADHD or bipolar disorder. All studies used structured psychiatric diagnostic interviews, cognitive and neuropsychological tests and psychosocial and global functioning measures to assess the probands and their first-degree relatives. State of the art statistical techniques will be employed.